Cholesterol lowering supplement

ABSTRACT

The invention provides a composition and a method for lowering blood serum cholesterol levels or for preventing elevated blood serum cholesterol levels, as well as a suitable composition comprising (a) one or more phytosterols and/or phytostanols capable of reducing cholesterol absorption in the intestine and/or one or more soluble fibres capable of inhibiting ileal bile acid absorption, (b) a composition capable of inhibiting cholesterol biosynthesis, and (c) a composition capable of increasing cholesterol metabolism, wherein at least one of compositions (b) and (c) is preferably derived from plants.

BACKGROUND OF THE INVENTION

Cardiovascular diseases (CVD) are the major cause of death anddisability in industrialised countries, despite recent declines in CVDmortality rates. They account for more deaths annually than any otherdisease, including all forms of cancer combined. In the USA more than 1million heart attacks occur each year and more than half a millionpeople still die as a result. This enormous toll has focused attentionon the possible prevention of CVD by various means, especially throughlowering of plasma cholesterol levels. It is well established now thatelevated total cholesterol, and in particular low-density lipoprotein(LDL) cholesterol, in plasma plays an important role in the developmentof atherosclerosis. Clinical trials have demonstrated clearly thatdecreasing cholesterol concentrations in plasma can contribute toprimary and secondary prevention of coronary events and mortality. Somestudies have estimated. a 2% reduction in risk of a coronary arteryevent by a 1% reduction of total serum cholesterol. Levi, 1..L,Declining Mortality in Coronary Heart Diseases, Artherosclerosis, 1981,1, 312-325.Cholesterol Adult Treatment Panel: Report of the NationalCholesterol Education Program Expert Panel on Detection, Evaluation andTreatment of High Cholesterol in Adults, Arch. Intern. Med., 1988, 148,36-69.Frick, M.H., et al., Primary prevention Trial with Gemfibrozil inMiddle-aged Men with Dyslipidemia: Safety of Treatment, Changes in RiskFactors, and Incidence of Coronary Heart Disease. New Engl. J. Med.,1987, 317, 1237-1245. Pederson T.R. et al., Randomised Trial ofCholesterol Lowering in 4444 Patients with Coronary Heart Disease: TheScandinavian Simvastatin Survival Study (4S), The Lancet, 1994, 344,1383-1389,La Rosa, J.C. et al, The Cholesterol Facts: A Summary of theEvidence relating to Dietary Fats, Serum Cholesterol and Coronary HeartDisease: A Joint Statement by the American Heart Association and theNational Heart, Lung and Blood Institute, Circulation, 1990, 81,1721-1733. Law, M.R. et al, By how much and how quickly does Reductionin Serum Cholesterol Concentrations lower Risk of Ischemic HeartDisease? Br. Med. J., 1994, 308, 367-373.

Serum cholesterol levels can for example be lowered by a daily intake ofsome components similar to cholesterol. The components similar tocholesterol reduce the absorption of cholesterol from the intestinesinto the bloodstream.

U.S. Pat. No. 5,958,913 discloses a substance comprising a saturatedsterol fatty acid ester capable of lowering LDL cholesterol levels inserum and which is fat soluble. The substance can be taken orally as afood additive, food substitute or supplement. A daily consumption ofsaturated sterol fatty acid ester in an amount between about 0.2 andabout 20 g/day has been shown to reduce the absorption of endogeniccholesterol.

Dietary fibres have been described to lower serum cholesterol levels.Dietary fibres can be classified in two major groups depending on theirsolubility in water. Structural fibres like lignin, and cellulose areinsoluble, whereas natural gel-forming fibres like pectins and gums aresoluble. Soluble fibres play an important role in lowering serumcholesterol. There are different mechanisms by which soluble fibreslower blood cholesterol, e.g. by increasing faecal bile acid excretion.Brown L, Rosner B, Willett WW, Sacks FM. Cholesterol-lowering effects ofdietary fibre: a meta-analysis. Am I Clin Nun. 1999;69(1):30-42.

Soluble fibres increase faecal bile acid excretion by severalmechanisms: 1) binding bile acids, 2) forming gels or highly viscoussolutions in the intestine and interfering with micelle formation (3).Soluble fibres are able to interact with bile acids, which results in anincreased faecal excretion of bile acids. Bile acids are derived fromcholesterol, and are normally effectively recycled by reabsorption fromthe ileum and resecretion by the liver as bile salts. To the extent thatbile acids are lost with the faeces, the liver must replace the lostbile salts using cholesterol. The viscosity and gelling properties ofsoluble fibres may have important effects on the hydrolysis andabsorption of cholesterol and the absorption of bile acids in the smallintestine. Fibres that increase the viscosity of the intestinal contentsmay decrease intestinal motility, thereby decreasing the mixing ofnutrients, digestive enzymes, and other intestinal components which willresult in decreased micelle formation and absorption. Anderson 1W,Desiring DE, Brid_(g)es SR. Soluble Fibre. Hypocholestorolernic Effectsand Proposed Mechanisms, p. 339-363.

Alternatively, compositions that inhibit the cholesterol biosynthesis,for example by inhibiting enzyme 3-hydroxy-3-methylglutaryl coenzyme Areductase (HMG-CoA reductase), an enzyme involved in the cholesterolbiosynthesis, can lower blood serum cholesterol by slowing down theproduction of cholesterol. It is believed that inhibition of HMG-CoAreductase results in a reduction in hepatic cholesterol synthesis andintracellular cholesterol stores, a compensatory increase in low-densitylipoprotein (LDL) receptors, and a subsequent enhanced removal ofLDL-cholesterol from plasma. Potent inhibitors of HMG-CoA reductaseinclude for example the compounds referred to as statins, which familycomprises for example lovastatin, pravastatin and fluvastatin.

Several studies suggested a HMG-CoA reductase inhibiting effect of plantextracts. Wang et al. demonstrated HMG-CoA reductase inhibition byseveral aqueous plant extracts in isolated rat hepatic microsomalpreparations. In vivo studies on rats demonstrated the inhibitory effectof traditional Chinese herbs on the cholesterol biosynthesis. Wang, S.L. et al, Effects of Flos Chrysanthemum and several other Chinese herbson in vitro HMGR activity of liver microsome of rest. Chinese 1. ofbiochemistry, 1988, 4(6): 517-522.Wang, S. L. at al., Effects of FittsChrysanthemum and other fourteen Chinese herbs on metabolism ofcholesterol in rats. Chinese J. of biochemistry, 1987, 3(4):319-323.

An enzyme involved in the cholesterol metabolism (conversion ofcholesterol into other components) is cholesterol 7α-hydroxylase.Hepatic cholesterol 7α-hydroxylase catalyses the conversion ofcholesterol into 7α-cholesterol, which is believed to be therate-limiting step in conversion of cholesterol into bile acids. It hasbeen suggested that the increase of cholesterol 7α-hydroxylase activityresults in the decrease of blood serum cholesterol and thus is animportant pathway of elimination of cholesterol from the body. Methodsfor treatment of blood serum cholesterol related disorders by inhibitionof cholesterol 7α-hydroxylase are known in the art.

WO 91/15213 discloses a method for treatment of cholesterol gallstonesemploying side-chain hydroxylated cholesterol derivative. In particularthe method for treatment of cholesterol gallstones involves theadministration of 25- or 26-hydroxycholesterol, which enhance theactivity of cholesterol 7α-hydroxylase, thereby inhibiting for examplecholesterol precipitation. Additionally, Wang et al. showed that severalherbal preparations are capable of increasing cholesterol 7α hydroxylaseactivity.

According to Raicht et al., feeding cholesterol to rats increasedcholesterol absorption from 1.2 to 70 mg/day and inhibited its synthesisin the liver and enhanced conversion of cholesterol to bile acids from13.7 to 27.3 mg/day, Furthermore, when given cholesterol to the rats,HMG-CoA reductase activity was inhibited 80%. With beta-sitosterol,cholesterol absorption was inhibited but cholesterol synthesis wasincreased from 20.0 to 28.8 mg/day. Raicht, R. F et al., Sterol balancestudies in the ra_(t). Effects of dietary cholesterol and beta-sitosterol on sterol balance and rate-limiting enzymes of sterolmetabolism. Biochimica at Biophysica Acta, 1975, 388(3): 374-384.

The majority of cholesterol lowering compositions currently known in theart include ingredients which either lower cholesterol absorption withinthe intestines or inhibit cholesterol biosynthesis, e.g. by inhibitionof HMG-CoA reductase. As Raicht et alY demonstrated, the inhibition ofcholesterol absorption in the intestine (using β-sitosterol) lowerscholesterol absorption, however, the inhibition of cholesterolabsorption in the intestines is followed by an increase in HMG-CoAreductase activity. Increase of the HMG-CoA reductase activity is likelyto increase cholesterol biosynthesis and thereby reduce the net effectof cholesterol absorption inhibitors. It is therefore desirable todecrease serum cholesterol levels using combination compositions, whichreduce cholesterol absorption within the intestine and additionallyinhibit cholesterol biosynthesis, e.g. by inhibiting HMG-CoA reductaseactivity.

Methods of reducing plasma cholesterol levels comprising administering acombination of an effective amount of cholesterol biosynthesis inhibitorand an effective amount of cholesterol absorption inhibitor aredisclosed in U.S. Pat. No. 5,661,145. The administered combinationincludes a beta-lactam cholesterol absorption inhibitor and a HMG-CoAreductase inhibitor, which can for example be a statin, for examplelovastatin or pravastatin. Other pharmaceutical combination compositionsincluding certain cholesterol absorption inhibitors and cholesterolsynthesis inhibitors useful for the treatment of hypercholesterolemiaand atherosclerosis are described in U.S. Pat. No. 5,807,834.

WO 98/01759 describes a method of determining in an animal the ratio ofserum campesterol to the level of β-sitosterol comprising several steps.Additionally, a combination composition for enhancing in an animal theinhibitory effect of phytosterols on cholesterol enterocyte absorption,which comprises one or more phytosterols which inhibit predominantly oneor both of cholesterol and beta sitosterol and one or more compoundswhich limit cholesterol synthesis, e.g. compounds selected form HMG CoAreductase inhibitors, for example lovostatin, is described. Furtherdescribed is the main disadvantage of the above composition i.e. the useof statins, and the critical side effects related with the use ofstating.

WO 00/15201 discloses a composition for preventing and treating CVDcontaining phytosterols or phytostanols as agents inhibiting cholesterolabsorption and tocotrienols as agents suppressing cholesterolbiosynthesis.

WO 00/38725 provides combinations of cardiovascular therapeuticcompounds for the prophylaxis or treatment of cardiovascular diseaseincluding hypercholesterolemia and atherosclerosis. Combinationsdisclosed include an ileal bile acid transport inhibitor combined with acholesteryl ester transport protein inhibitor, a fibric acid derivative,a nicotinic acid derivative, a microsomal triglyceride transfer proteininhibitor, a cholesterol absorption antagonist, or others. Furthercombinations include a CETP inhibitor with a brio acid derivative, anicotinic acid derivative, a bile acid sequestrant, a microsomaltriglyceride transfer protein inhibitor, a cholesterol absorptionantagonist, or others.

U.S. Pat. No. 5,958,417 describes a herbal combination comprisingCrataegus, Ho Shot; Wu, Cassia Seed, Chrysanthemum, Lotus Leaf, Alisma,Hu-Zhang, and Rhubarb wherein the herbs are present in specif_(i)cweight percentages. However, the herbal combination lacks a potentcholesterol absorption-inhibiting component.

Notwithstanding these disclosures, there remains a need in the art forcompositions for use in reduction of blood serum cholesterol levels orprevention of elevated blood serum cholesterol levels. Combinationcompositions including cholesterol absorption inhibitors and cholesterolsynthesis inhibitors useful for reduction of blood serum cholesterollevels known in the art are mostly chemically manufactured compositionsand the known compositions are therefore undesirable for many people,not natural and costly.

Additionally, the combination compositions known in the art cannot beused frequently for a longer period since negative side effects willoccur. Recent studies have indicated that drugs like statins, often usedas HMG-CoA reductase inhibitors in combination compositions, andfibrates can be carcinogenic or cause other undesirable side effects.Newman et al reported that all members of the classes statins andfibrates cause cancer in rodents. Furthermore, two hyperlipidemicpatients treated with simvastatin, a potent inhibitor of HMG-CoAreductase, experienced cheilitis after beginning treatment. The rashresolved after discontinuation of medication and subsequent treatmentwith topical moisturisers and topical corticosteroids (Mehregan at al.).Khosla et al alerts clinicians to the possible adverse effect ofsimvastatin and other statins by reporting a case of a 79-year-old manwho had onset of fatigue, myalgia, and pleuritic chest pain 3 monthsafter initiation of therapy with simvastatin. Lovastatin was reported tocause liver failure (Tolmau). Newman et al., Carcinogenicity oflipid-lowering drugs. JAMA, 1996275(1): 55-60.Mehregan D. R. at al.,Cheilitis due t_(o) treatment with simvastatin. Cutis, 1998,62(4):197-198.Koshla R. at al, Simvastatin-induced lupus erythematosus.South Med, Y., 1998, 91(9):873-874.Tolman K. G., Def_(i)ning patientrisks from expanded preventive therapies. Am, J. Cardiol, 2000, 85(12A):15E-9E.

Furthermore, combination compositions known in the art to . date onlycomprise effective amounts of at most two of the blood serum cholesterolreducing activities, selected from reduction of cholesterol absorptionin the intestine, inhibition cholesterol of biosynthesis and increase ofcholesterol metabolism.

SUMMARY OF THE INVENTION:

The present invention overcomes the above problems and providescombination compositions for use in reduction of blood serum cholesterollevels or prevention of elevated blood serum cholesterol levels.comprising one or more phytosterols and phytostanols capable of reducingcholesterol absorption in the intestine, and/or soluble fibres andmixtures thereof, capable of inhibiting ileal bile acid absorption, andan effective amount of a plant derived composition capable of inhibitingcholesterol biosynthesis and an effective amount of a plant derivedcomposition capable of increasing cholesterol metabolism.

The combination composition disclosed here fulfils the need forcholesterol-reducing combinations having plant-derived activecomponents. The composition according to the invention can therefore beadministered for a longer period, thus making it suitable for use incompositions for reduction of blood serum cholesterol levels orprevention of elevated blood serum cholesterol levels. The inventionprovides a balanced composition ibr use in reducing blood serumcholesterol levels or preventing elevated blood cholesterol levels.These combination compositions avoid the potential side effects orcompensatory effects associated with the administration of relativelyhigh levels of components solely directed at reducing cholesterolabsorption in the intestine or at inhibiting cholesterol synthesis or atincreasing cholesterol metabolism, or at only two of those threemechanisms.

The present invention provides a composition for use in reduction ofblood serum cholesterol levels or prevention of elevated blood serumcholesterol levels comprising:

a. one or more compounds capable of reducing cholesterol absorption inthe intestine and/or inhibiting ileal bile acid absorption, selectedfrom phytosterols and phytostanols and soluble fibres and mixturesthereof,

b. an effective amount of a composition capable of inhibitingcholesterol biosynthesis,

c, an effective amount of a composition capable of increasingcholesterol metabolism.

Advantageously, at least one of compositions (b) and (c) is derived fromplants, i.e, obtained by extraction of plants, using water,water/alcohol mixtures, alcohols, hydrocarbons or halogenatedhydrocarbons as extracting liquids. Preferably, both composition (b) andcomposition (c) are derived from plants, most preferably from differentplants or different combinations of plants.

A further object of the present invention is to provide a method ofreducing serum cholesterol levels or preventing elevated blood serumcholesterol levels comprising, administering to a person a compositioncomprising one or more phytosterols and/or phytostanols and/or solublefibres, capable of reducing cholesterol absorption in the intestineand/or capable of inhibiting ileal bile acid absorption, an effectiveamount of a plant derived composition capable of inhibiting cholesterolbiosynthesis and an effective amount of a plant derived compositioncapable of increasing cholesterol metabolism.

DESCRIPTION OF THE INVENTION

The term cholesterol biosynthesis is well-known in the art and generallyrefers to the biochemical pathways of cholesterol synthesis within theanimal (e.g. human) body. The term cholesterol metabolism is alsowell-known in the art and generally refers to the biochemical pathwaysinvolved in the removal of cholesterol from the body.

The phytosterol and/or phytostanol or mixtures thereof capable ofreducing cholesterol absorption in the intestine can be any compositionof phytosterol and/or phytostanol or mixtures thereof known in the artand having a cholesterol absorption reducing effect. Phytosterols aresteroids derived from plants, yeasts or fungi, which have a hydroxylgroup at C-3 and no other functional groups and differ from animalsterols, in particular cholesterol, in that the side chain at position17 contains a double bond and/or an additional methyl, ethyl orethylidene group, in particular at position 24. The term phytosteroland/or phytostanol according to the invention, comprises all suchanalogues, which may further have a double bond at the 5-position in thecyclic unit as in most natural phytosterols, or one or more double bondsat other positions (e.g. 6, 7, 8(9), 8(14), 14, 5/7, or no double bondsin the cyclic unit E S1 1 the steno's, or even additional methyl groupsas e.g. in a_(t) -sitosterol; the term includes natural phytosterols andderivatives thereof.

According to a preferred embodiment the phytosterol and/or phytostanolsor mixtures thereof are obtained from vegetable oil or wood pulp. Morein particular, α-, β-, γ-sitosterol, stigmasterol, ergosterol,campesterol, avenasterol, brassicasterol, desmosterol, elialinosterol,poriferasterol, clionasterol, sitostanol, stigmastanol, campestanol or amixture of one or more of the above phytosterols and phytostanols isused. According to an even more preferred embodiment, sitosterol ormixtures including a sitosterol are used. The concentration ofphytosterols and/or phytostanols in composition (a) is at least 10%,preferably at least 25%, more preferably at least 50%, most preferablyat least 80% by dry weight of composition (a).

The soluble fibre capable of inhibiting ileal bile acid absorption canbind ileal bile acids in the intestine, thereby preventing or reducingthe re-absorption of bile acids. The term soluble fibre refers to fibreswhich are not digested by the acids or enzymes in the digestive tract,but are fermented by the intestinal bacteria and are soluble in water.The soluble fibre of the present invention is preferably selected fromthe group consisting of pectin, cbitosan, β-glucan, such asβ-1,6-glucan, especially β-1,3-glucan, soluble fibre from psyllium husk(hereafter referred to as psyllium), xanthan gum, guar gum, locust beangum, gum arabic, soy fibre and mixtures thereof, more preferably fromthe group consisting of psyllium, pectin, (β-glucan and mixturesthereof, even more preferably the soluble fibre is β-glucan. The(β-glucan soluble fibre is preferably obtained from whole oat, and evenmore preferably is part of a whole oat soluble fibre composition.Derivatives and modifications of the soluble fibres, especiallyhydrolysates, can also suitably be used in the compositions of theinvention.

Preferably, the polysaccharides of the fibres or their hydrolysates havean average chain length of at least 20, preferably at least 100 monoseunits. In a particular embodiment, the fibre comprises β-glucan togetherwith at least one member selected from pectin, xanthan gum, guar gum,locust bean gum and gum arabic, preferably in a ratio between 9:1 and1:9.

Preferably, the soluble fibre is administered in an amount between 0.2 gand 100 g soluble fibre per day, more preferably between 0.5 and 50 g,even more preferably between 1 and 25 grams, most preferably between 2and 10 grams per day. The β-glucan is preferably administered in anamount between 0.5 and 30 gram, more preferably in an amount between 0.6and 10 gram, even more preferably in an amount between 0.7 and 8 gram.

Table 1 gives the preferred and the most preferred daily amounts for thesoluble fibres when each soluble fibre preparation is administered asthe sole soluble fibre source. The quantities of these fibres may bereduced when combinations of soluble fibres are administered.

TABLE 1 Preferred range Most preferred range Soluble fibre (g/day)(g/day) pectin 0.5-20 1-15 chitosan 0.4-25 1-20 β-glucan 0.5-20 0.7-8  whole oat soluble fibre 0.5-30 0.7-8   psyllium 0.5-30 1.6-10   xanthangum 0.75-35  1-30 soy fibre   1-40 3-30 locust bean gum 0.5-40 1-35 gumArabic   1-50 2-40 guar gum   1-40 2-25

The soluble fibre may be mixed with the composition capable ofinhibiting cholesterol biosynthesis and the composition capable ofincreasing cholesterol raetabolism prior to administration. The fibreincluding serum cholesterol-lowering mixture may also containphytosterols, phytostano1s or mixtures thereof Alternatively, andpreferably, the soluble fibre is administered separately from acomposition comprising a composition capable of increasing cholesterolmetabolism and a composition capable of inhibiting cholesterolbiosynthesis. Thus, the composition according to the invention can be asingle mixture, or it can be a combination of two or more physicallyseparated mixtures.

Preferably, the composition comprising a composition capable ofincreasing cholesterol metabolism and a composition capable ofinhibiting cholesterol biosynthesis is provided in the form of a pill,capsule or tablet and the soluble fibre composition is provided as apowder, emulsion, suspension, syrup or elixir. The pill, capsule ortablet preferably has a weight between 0.1 and 5 g, more preferablybetween 0.2 and 4 g, especially between 0.5 and 2.5 g. The powder,emulsion, suspension, syrup or elixir preferably has a weight of between200 mg and 100 g, preferably between 1 and 15 g, dry weight. The amountsgiven for the pills, capsules, powders etc., may be provided in a singledaily dose unit, or be divided over multiple (e.g. 2-4) daily doseunits.

The plant-derived composition capable of inhibiting cholesterolbiosynthesis according to the invention preferably comprises acomposition capable of inhibiting the enzyme 3-hydroxy-3-methylglutarylcoenzyme A reductase (HMG-CoA reductase inhibitor) and/or inhibitingsqualene synthase (squalene synthase inhibitor). HMG-CoA reductaseinhibitors can decrease the activity of HMG-CoA reductase, thusinhibiting the conversion of HMG-CoA, to mevalonate. The HMG-CoAreductase inhibitors can act on the HMG-CoA reductase directly orindirectly by decreasing the activity of one or more enzymes (e.g.HMG-CoA reductase phosphatase) or cofactors involved in the activationof HMG-CoA reductase or increasing the activity of one or more enzymes(e.g. HMG-CoA reductase kinase) or cofactors involved in the downregulation of HMG-CoA reductase or by decreasing the of HMG-CoAreductase gene transcription or of HMG-CoA reductase RNA translation.

Squalene synthase inhibitors can decrease the activity of squalenesynthase, thus inhibiting the conversion of faruesyl pyrophosphate intosqualene. Squalene synthase inhibitors can act on the squalene synthasedirectly, or indirectly by decreasing the activity of one or moreenzymes or cofactors involved in the activation of squalene synthase; orincreasing the activity of one or more enzymes or cofactors involved inthe down regulation of squalene synthase; or decreasing the squalenesynthase gene transcription or squalene synthase RNA translation.According to a preferred embodiment the composition capable ofinhibiting cholesterol biosynthesis comprises one or more HMG-CoAreductase inhibitors.

The composition capable of inhibiting cholesterol biosynthesis ispreferably obtained from whole plants or from one or more parts thereof,for example stems, stalks, roots, shoots, rhizomes, tubers, fruits,foliage, kernels, husks, hulls or mixtures thereof. Preferably, thecomposition is an extract from whole plants or plant parts. Suchextracts can be obtained by harvesting the plants, optionallycomminuting the plants and/or separating certain parts of the plants,drying, extracting the plants or plant parts using liquid extraction,and optionally concentrating the extract. Drying of the plants isusually necessary to avoid degradation of labile components or microbialcontamination upon storage, transport or processing, and results inlowering the water content from e.g. 50-90% to e.g. less than 25%,preferably less than 20%, most preferably between 5 and 15%. Drying isperformed under mild conditions i.e. at temperatures between 0 and 80°C., in particular between 10 and 60° C., or by freeze-drying. Before orafter drying, the plants or plant parts may be reduced in particle sizeto coarse fragments or even to fine powder by processes such asgrinding, flaking or mincing. Grinding using a hammer mill or equivalentmachine is preferred. Extraction according to the invention refers toseparating the desired plant material by physical or chemical means,preferably with the aid of a solvent. Suitable solvents include water,water-alcohol mixtures, alcohols, ethers, hydrocarbons or other organicsolvents or mixtures thereof. Water and water-based solvent mixtures arepreferred. Extraction can be performed by maceration, i.e. soaking for atime between e.g. one minute and several hours, optionally usingagitation, followed by filtration. For larger scale operations,counter-current extraction can be used. The resulting solutions can beconcentrated to liquid or solid extracts using e.g. thin layerevaporators, freeze-drying or spray-drying techniques. Spray-dryingresulting in concentrated to dry powders is preferred. Suitable plantextracts containing inhibitors of cholesterol biosynthesis arecommercially available.

Preferred sources for the composition capable of inhibiting cholesterolbiosynthesis include Alisma orienwle (pharmaceutical name Rhizomealismatis); Typha spp., for example Typha angustifolia or Typhaorientalia (pharmaceutical name Pollen Typhea); Salvia miltiorhiza(pharmaceutical name Radix salviae railtiorrhine); Polygonummultiflorurn (pharmaceutical name Radix Polygoni multiflora); Curcwnaspp., for example C. kwangsiens-is, C. longa, C. phaecaulis, C. wenyuinor C. aromatica, (pharmaceutical name Radix curcurnae or Rhizomecurcuraae); Ligusticwn spp., for example L. Wallichii, (pharmaceuticalname Rhizome Ligustici); Polygoncrtum app., for example P. kingianwn, P.sibiricurn or P. cyrtonerna (pharmaceutical name Rhizome polygonati);Polygonum cuspidation (pharmaceutical name Rhizome polygoni cuspidati);Corydcdis spp. (pharmaceutical name Rhizome Corydalis); Chrysanthemumnzonfolium (pharmaceutical name Flos Chrysanthemi); Arthemisiacapillaris (pharmaceutical name Herba Artimisiae capillaris); Crataegusphmatifida or its variations or subspecies (pharmaceutical name FructusCrataegi pimiatifidae); Eleutheroccus senticocus (pharmaceutical nameRadix eleutherococci senticosi); Astragalus membranaceus (pharmaceuticalname Radix Astragali). According to a particularly preferred embodiment,Polygonum multiflorum is used as a source for the composition capable ofinhibiting cholesterol biosynthesis, more preferably an aqueous extractof Polygonum multiflorum.

Preferably, the composition capable of increasing cholesterol metabolismincreases the conversion of cholesterol into bile acids and/or inhibitsthe esterification of cholesterol. According to an even more preferredembodiment, the composition capable of increasing cholesterol metabolismenhances the activity of cholesterol 7α-hydroxylase (cholesterol-7αhydroxylase activator) and/or inhibits the activity of Acyl-CoA acyltransferase (Acyl-CoA acyl transferase inhibitor),

A cholesterol 7α-hydroxylase activator can enhance the activity ofcholesterol 7α-hydroxylase, thus enhance the conversion of cholesterolinto 7a-cholesterol. Cholesterol 7α-hydroxylase activators can act onthe cholesterol 7a-hydroxylase directly or indirectly by increasing theactivity of enzymes and cofactors involved in the activation ofcholesterol 7α-hydroxylase or decrease the activity of enzymes orcofactors involved in the down-regulation of cholesterol 7α-hydroxylase(e.g. by effecting enzymes involved in the phosphorylation anddephosphorylation of cholesterol 7α-hydroxylase) or increasing thecholesterol 7α-hydroxylase gene transcription or cholesterol 7αhydroxylase RNA translation.

Acyl-CoA acyl transferase inhibitors can inhibit the conversion ofcholesterol into cholesteryl oleate. Acyl-CoA acyl transferaseinhibitors can act on the Acyl-CoA acyl transferase directly, orindirectly by decreasing the activity of one or more enzymes orcofactors involved in the activation of Acyl-CoA acyl transferase orincreasing the activity of one or more enzymes or cofactors involved inthe down regulation of Acyl-CoA acyl transferase or decreasing theAcyl-CoA acyl transferase gene transcription or Acyl-CoA acyltransferase RNA translation. According to a preferred embodiment, thecomposition capable of increasing cholesterol metabolism comprises oneor more cholesterol 7α-hydroxylase activators, which act systemically.

The composition capable of enhancing cholesterol metabolism ispreferably obtained from whole plants or from one or more parts thereof,for example stems, stalks, roots, shoots, rhizomes, tubers, fruits,foliage, kernels, biers. hulls or mixtures thereof The whole plants orplant parts providing enhancers of cholesterol metabolism may besubjected to extraction as described above for plants providinginhibitors of cholesterol biosynthesis. Suitable extracts containing theplant-derived metabolic enhancers are commercially available.

Preferred sources for obtaining the compositions capable of increasingcholesterol metabolism include Polygonum multiflorurn (pharmaceuticalname Radix Polygord is multiflora); Curcuma spp., for example C.kwangsiensis, C. longs, C. phaecaulis, C. wenyuin or C. aromatica,(pharmaceutical name Radix curcumae or Rhizome curcumae); Ligusticwnspp., for example L. wallichii, (pharmaceutical name Rhizoma Ligustici);Polygonatum spp., for example P. kingianum, P. sibiricum or P. cyrtonema(pharmaceutical name Rhizome polygonati); Polygonum cuspidatum(pharmaceutical name Rhizoma polygoni cuspidal); Corydalis spp.(pharmaceutical name Rhizoma Corydalis); Chrysanthemum morifolium(pharmaceutical name Flos Chrysanthemi); Arthernisia capillaris(pharmaceutical name Rerba Artimisiae capillaris); Acanthopanaxsenticosus (pharmaceutical name Radix Astragali). According to aparticularly preferred embodiment Chrysanthemum morifolltmi is used as asource for the composition capable of increasing cholesterol metabolism,more preferably an aqueous extract Chrysanthemum morifollum.

The dry weight ratio between composition (a) and the combination ofcompositions (b) and (c) is preferably between 10:1 and 1;10, morepreferably between 4:1 and 1:4, if (a) does not contain soluble fibre;if (a) contains soluble fibre, the dry weight ratio between (a) and (b)+(c) is preferably between 100:1 and 1:5, more preferably between 30:1and 1:1. The dry weight ratio between compositions (b) and (c) ispreferably between 10:1 and 1:10, more preferably between 3:1 and 1:3.If composition (a) contains both (a1) phytosterols and/or phytostanolsand (a2) soluble fibre, the weight ratio between the (a1) and (a2) ispreferably between 1:100 and 5:1, more preferably between 1;50 and 1:2.

Elevated serum cholesterol levels are often closely related to a reducedvascular health. It is therefore advantageously to include in thecomposition for use in reduction of blood serum cholesterol levels orprevention of elevated blood serum cholesterol levels, an effectiveamount of a composition for the prevention and/or treatment of vasculardisorders. Preferably one or more compounds selected from the group ofpolyunsaturated fatty acids, antioxidants, phospholipids, folic acid,vitamin B12, vitamin B6, magnesium, coenzyme Q10 and zinc are includedin the composition according to the invention. These compositions mayserve as additives or potentiators, thus increasing the cholesterollowing effect of phytosterols and/or to phytostanols, and/or fortreatment and prevention of vascular disorders. Preferredpolyunsaturated fatty acids are omega-6-fatty acids or omega-3-fattyacids or mixtures thereof, for example eicosapentaenoic acid,docosahexaenoic acid or linoleic acid. As a preferred antioxidant, atocopherol, for example vitamin E, is used As a preferred phospholipid,lecithin is used.

According to an even further preferred embodiment, long chainpolyunsaturated fatty acids, phospholipids and a compound selected fromthe group of folic acid, vitamin B12, vitamin B6, magnesium, zinc areincluded in composition for use in reduction of blood serum cholesterollevels or prevention of elevated blood serum cholesterol levels

The composition according to the invention is preferably administeredorally. The composition can for example be added to food or feedproducts such as beverages or products with a substantial oil content oringested as nutritional supplement in the form of for example tablet,capsule, microbead, emulsion, powder, granule, suspension, syrup,elixir, chewing gums and the like.

Preferred daily intake amounts of the components according to theinvention greatly depend on the concentration of available and/or activecomponent present in the composition. This is especially applicable forthe plant-derived material capable of inhibiting cholesterolbiosynthesis and the composition capable of increasing cholesterolmetabolism. According to a preferred embodiment, the daily dose of thecomposition according to the invention includes about 0.01 to 5 gramphytosterol and/or phytostanol or mixtures thereof; more preferablyabout 0.1 to 1 gram, most preferred about 0.2 to 0.6 gram. Thecomposition capable of inhibiting cholesterol biosynthesis preferablycomprises per daily dose about 0.01 to about 30 gram, depending on thetype of herbal preparation used. For example, when using crudepreparations of Polygoman multiflorum, e.g. unprocessed root, the dailyintake is preferably between about 0.5 gram and about 15 gram. Whenprocessed Polygonum multiflorum is used (the process for preparation ofprocessed Polygonum multiflorum is well known in the art and reducesLD50 value of Polygonum multlflorum compared to crude Polygonumrnultifjorum), the daily intake is preferably between about 0.5 gram andabout 30 gram. According to a preferred embodiment of this invention,concentrated extracts of one or more of the plant sources are used.According to a further preferred embodiment, a concentrated extract ofPolygonum multiflorum is used, corresponding to about 0.5 to about to 30gram crude Polygonum mulaflorum, preferably about 3-10 gram crudePolygonum multiflorum. Thus when using an aqueous extract having aconcentration ratio of 16:1 (16 times concentrated), the daily intake ispreferably about 0.05 gram to about 2 grams, even more preferably about0,1 gram to about 0.7 gram of the extract.

The composition capable of increasing cholesterol metabolism preferablycomprises per daily dose about 0.01 to about 30 gram depending on thetype of herbal preparation used. For example, when using crudepreparations of Chrysanthemum tnorgblium, e.g. unprocessed flower, thedaily intake is preferably about 1 gram to about 15 gram. According to apreferred embodiment, a concentrated extract of Chrysanthemum morifoliumis used corresponding to about 1-15 gram crude Chrysanthemum morifolium,preferably about 3-10 gram crude

Chrysanthemum: morifolium. Thus when using an aqueous extract ofChrysanthemum morifoliwn having an concentration ratio of about 10:1 (10times concentrated), the daily intake is preferably about 0.01 gram toabout 3 grams, even more preferably about 0.1 gram to about 0.7 gram ofthe extract.

Example 1: Capsule composition

A capsule comprising:

500 mg phytosterol mixture; including about brassioasterol (6%),campesterol (30%), stigmasterol (22%), sitosterol (58%).

250 mg concentrated Radix Polygoni multiflora water extract withconcentration ratio of 16:1 (obtainable form P.L. Thomas & Co., Inc,having adress Morristown, NI 07980)

200 mg Flos Chrystmthemi extract (obtainable form MTC Nutrioions, Inc,Whitestone, NY 11357).

Three capsules per day is the recommended treatment.

Example 2: Capsule composition B

A capsule comprising: 500 mg phytosterol mixture; including aboutbrassicasterol (6%), campesterol (30%), stigmasterol (22%), sitosterol(58%).

250 mg Radix Polygoni multiflora extract

200 mg Flos Cbrysantherai extract

400 mg lecithin

60 mg eicosapentaenoic acid

60 mg docosahexaenoic acid,

Three capsules per day is the recommended treatment,

Example 3: Capsule composition Ill

The capsule described in example 1, further comprising:

1000 mg soybean oil

150 mg laurio acid and monoolein.

Three capsules per day is the recommended treatment.

Example 4: Capsule composition IV

The capsule described in example 2, further comprising:

400 IU vitamin E.

Example 5: Treatment and prevention of high cholesterol leve

Administering to a subject showing a high risk of elevated serumcholesterol

a capsule containing 250 mg Radix Polygoni multiflora extract and 200 mgFlos chrysanthemi extract and

a sachet containing water and soluble fibre mixture providing

645 mg Pectin 1888 mg  Guar Gum 991 mg Gum Arabic 921 mg Locust Bean Gum 60 mg Beta-glucan 537 mg Oat Fibre

Two capsules and one sachet per day is the recommended treatment,

Example 6: Capsule composition V

A capsule comprising

250 mg Radix polygoni multi/lora extract

200 mg Nos Chrysanthemi extract

750 mg oat (3-glucan. Three capsules per day is the recommendedtreatment.

1. A composition comprising: (a) one or more soluble fibres capable ofinhibiting ileal bile acid absorption; (b) a composition capable ofinhibiting cholesterol biosynthesis; (c) a composition capable ofincreasing cholesterol metabolism; wherein at least one of compositions(b) and (c) is obtained from plants.
 2. A composition according to claim1, wherein at least one of compositions (b) and (c) is an extract from aplant or plant parts.
 3. A composition according to claim 2, whereincompositions (b) and (c) are extracts from different plant or partsthereof.
 4. A composition according to claim 1, wherein composition (b)capable of inhibiting cholesterol biosynthesis comprises one or moreHMG-CoA reductase inhibitors and/or squalene synthase inhibitors,preferably one or more HMG-CoA reductase inhibitors.
 5. A compositionaccording to claim 4, wherein the composition (b) is derived from aplant or plant part selected from Alisma orientale, Typha spp., Salviamiltiorhiza, Polygonum multiflorum, Curcuma spp., Ligusticum spp.,Polygonatum spp., Polygonum cuspidatum; Corydalis spp; Chrysanthemummorifolium; Arthemisia capillaries; Crataegus pinnatifida, Eleutheroccussenticocus, Astragalus membranaceus and subspecies and varietiesthereof, the composition especially comprising an extract of Polygonummultiflorum.
 6. A composition according to claim 5, wherein composition(c) capable of increasing cholesterol metabolism is derived from a plantor plant part selected from Polygonum multiflorum, Curcuma spp.,Ligusticum spp., Polygonatum spp., Polygonum cuspidatum, Corydalis spp.,Chrysanthemum morifolium, Arthemisia capillaries and Acanthopanaxsenticosus; wherein compositions (b) and (c) are extracts from differentplants or parts thereof.
 7. A composition according to claim 1, whereincomposition (a) comprises between 10 mg and 100 g, per daily dosageunit, of one or more soluble fibres selected from pectin, chitosan,(3-glucan, psyllium, xanthan gum, guar gum, locust bean gum, gum Arabic,soy fibre and mixtures thereof, preferably comprising pectin and/or(3-glucan.
 8. A composition according to claim 1, wherein the weightratio between the fibres of composition (a) and the combination ofcompositions (b) and (c) is between 1:5 and 100:1.
 9. A compositionaccording to claim 1, wherein composition (a) further contains at least10% by dry weight of phytosterols and/or phytostanols capable ofreducing cholesterol absorption in the intestine.
 10. A compositionaccording to claim 9, wherein the phytosterol and/or phytostanol ormixture thereof comprises a plant sterol obtained from vegetable oil orwood pulp.
 11. A composition according to claim 9, comprising aphytosterol selected from sitosterol, stigmasterol, ergosterol,campesterol, avenasterol, brassicasterol, desmosterol, chalinosterol,poriferasterol, clionasterol, sitostanol, stigmastanol and campestanol.12. A composition according to claim 11, wherein the phytosterolcomprises a sitosterol.
 13. A composition according to claim 1, whereincomposition (c) capable of increasing cholesterol metabolism comprisesan effective amount of a composition capable of increasing conversion ofcholesterol into bile acids and/or inhibiting the esterification ofcholesterol.
 14. A composition according to claim 13, whereincomposition (c) comprises one or more cholesterol 7a-hydroxylaseactivators and/or one or more Acyl-CoA acyl transferase inhibitors. 15.A composition according to claim 14, wherein the composition capable ofincreasing cholesterol metabolism is derived from a plant or plant partselected from Polygonum multiflorum, Polygonum cuspidatum, Curcuma spp.,Ligusticum spp., Polygonatum spp., Corydalis spp., Chrysanthemummorifolium, Arthemisia capillaries and Acanthopanax senticosus, thecomposition especially comprising an extract of Chrysanthemummorifolium.
 16. A composition according to claim 1, further comprisingan effective amount of a component for the prevention and/or treatmentof vascular disorders.
 17. A composition according to claim 16, whereinthe component for the prevention and/or treatment of vascular disordersis selected from a polyunsaturated fatty acid preferably comprising anomega-6-fatty acid and/or an omega-3-fatty acid, antioxidants preferablycomprising vitamin E and/or another tocopherol, a phospholipidpreferably comprising lecithin, folic acid, vitamin B12, vitamin B6,magnesium, coenzyme Q10 and zinc.
 18. A food or beverage productcomprising a composition according to claim
 1. 19. A nutritionalsupplement comprising a composition according to claim
 1. 20. A tablet,capsule, microbead, emulsion, powder, granule, suspension, syrup, elixiror chewing gum comprising a composition according to claim
 1. 21. Amethod of reducing serum cholesterol levels or preventing elevated bloodserum cholesterol levels comprising administering to a person in needthereof an effective amount of: (d) at least 10 mg per day of one ormore phytosterols and/or phytostanols capable of reducing cholesterolabsorption in the intestine, and/or at least 10 mg per day of one ormore soluble fibres capable of inhibiting ileal bile acid absorption;(e) a plant-derived composition capable of inhibiting cholesterolbiosynthesis; and a plant-derived composition capable of increasingcholesterol metabolism.